The remarkable anticancer properties of dolastatin 10 (1), a unique pentapeptide that was isolated by one of the present inventors from the sea hare Dolabella auricularia, has led to intense interest in closely related derivatives (auristatins) that are suitable for clinical trial. Such structural modifications have provided a number of potential clinical candidates with enhanced efficacy and pharmacological characteristics. Replacement of the dolaphenine (Doe) unit with phenethylamides to give auristatins PE (2a), PHE (2b) and E (2c) and with pyridylethylamide (auristatin PYE) has led to active analogues that are undergoing preclinical and clinical development.
Dolastatin 10 and three of the auristatins are in human cancer clinical trials, ranging from phase I to phase III and N-des-methyl-auristatin E linked to a CD-30 monoclonal antibody is in marketing as ADCETRIS™.

Because of the potency of auristatins, they may be delivered linked to a monoclonal antibody. The linker to the monoclonal antibody is stable in extracellular fluid, but is cleaved once the conjugate has entered a tumor cell, thus activating the antimitotic mechanism at the site where it is most needed. In this way, antibody-drug conjugates (ADCs) made with auristatin antimitotic agents have been recognized as having significant preclinical and clinical oncology activity. SGN-75 is in clinical trials and is composed of an anti-CD70 antibody conjugated to monomethylauristatin F through a noncleavable maleimidocaproyl linkage.
Conjugation of auristatin drugs to antibodies, either directly or indirectly through linkers, involves consideration of a variety of factors, including the identity and location of the chemical group for conjugation of the drug, the mechanism of drug release, the structural elements providing drug release, and the structural modification to the released free drug. In addition, if the drug is to be released after antibody internalization, the mechanism of drug release must be consonant with the intracellular trafficking of the conjugate.
Given the promising results of SGN-75 as an agent as a therapeutic agent in clinical trials, there is a need to identify additional such agents for therapy.